Ischemic heart disease is a common and serious health problem. Every year, large numbers of patients die from ischemic heart disease and its complications. Many others experience acute myocardial infarcation, congestive heart failure, cardiac arrhythmias, or other disorders.
Myocardial ischemia exists when the heart tissue experiences a demand for oxygen and substrates that exceed the supply. Imbalances between oxygen supply and demand span a large range, and thus, there are various syndromes and biochemical pathways involved in the pathogenesis of ischemia, e.g., from low-grade to severe ischemic conditions. For example, chronic stable angina pectoris is a low-grade condition, in which the resting coronary blood flood may be normal but the blood flow reserve is insufficient to meet an increased energy demand. In more extreme situations, the ischemic muscle can develop an impaired contractile function and potential to generate arrhythmias. Major consequences of myocardial ischemia include mechanical and electrical dysfunction, muscle cell damage, and development of necrosis. Acute ischemic events may develop where there is coronary atherosclerosis. Ultimately, if the ischemia is sufficiently severe there will be an immediate reduction (or cessation) of contractile function in the heart.
The impairment of contractile function in ischemic muscle is associated with mitochondrial levels of adenosine triphosphate (ATP) and adenosine triphosphatases (ATPases). ATPases are enzymes that typically catalyze the hydrolysis of ATP, the main energy currency in cells, to adenosine monophosphate (AMP) or adenosine diphosphate (ADP), plus phosphate ions and energy. The contractile function of the heart is regulated by the transport of calcium, sodium, and potassium ions, which in turn is modulated by ATP and ATPases. More particularly, intracellular ATP is split by Na+,K+ATPase, an enzyme that is responsible for maintaining a gradient of sodium and potassium ions across the cell membrane. The splitting of ATP by Na+,K+ATPase releases the energy needed to transport K+ and Na+ ions against concentration gradients. This enables the existence of a resting potential in the membrane (i.e, Na+ out, K+ in) which initiates the contractile response. Contraction is triggered by Na/Ca exchange and Ca2+ transport, the energy for which is generated by the hydrolysis of ATP by Ca2+ ATPase.
To maintain homeostasis, the cells' supply of ATP must be replenished as it is consumed (e.g., with muscle contraction). During the steady state, the rate of ATP synthesis needs to be closely matched to its rate of consumption. Arguably, the most important ATPase is the mitochondrial F1F0-ATPase. Unlike other ATPases which function typically to hydrolyze ATP and release energy, the F1F0-ATPase has both hydrolytic and synthetic states. As “ATP synthase”, the mitochondrial F1F0-ATPase catalyzes the production of ATP via oxidative phosphorylation of ADP and Pi. Thus, F1F0-ATPase is responsible for producing the cell's main energy source, ATP. In normoxic conditions, mitochondrial F1F0-ATPase modulates this ATP production via its two units, the F1 and F0 complexes. F0 is the inner membrane domain, and F1 is a catalytic domain consisting of five subunits ((αβχδε—the catalytic site is on the β unit), that protrude from the F0 domain into the mitochondrial matrix. When sufficient levels of oxygen are present, electrons from ATPase substrates are transferred to oxygen, and protons are transported out of the mithcondrial matrix. This proton/electron transport creates an electrochemical proton gradient across the mitochondrial membrane and through the F0 domain which drives the F1 domain to synthesize ATP.
In ischemic conditions, however, this electrochemical gradient collapses, and F1F0-ATPase switches to its hydrolytic state. This hydrolysis of ATP seems to serve no useful purpose. Also, as F1F0-ATPase operates in its hydrolytic state there is a down-regulation of F1F0-ATP synthase. F1F0-ATP synthase activities in vesicles from ischemic muscle typically are substantially (up to ˜50-80%) less than those of control muscle. A native peptide called IF1 inhibitor protein (or IF1) may be bound to the F1 unit under ischemic conditions to inhibit the ATP hydrolase activity of the enzyme; however, IF1 is highly pH dependent and in severe conditions can provide only a modicum of control. The conversion of F1F0-ATP synthase to F1F0-ATP hydrolase is reversible, as addition of substrate and oxygen to the mitochondria of ischemic muscle can reactivate the F1F0-ATPase and ATP levels to control levels.
As may be appreciated, in ischemic conditions the activity of F1F0-ATPase produces a futile cycling and waste of ATP. It is believed that this depletion of ATP and/or ATP synthase may suppress the Na+K+ pump to increase cardiac contractility, vasoconstriction, sensitivity to vasoactive agents, and arterial blood pressure. Several inhibitors of F1F0-ATPase have been described, including efrapeptin, oligomycin, autovertin B, and azide. Oligomycin targets F0 and reportedly postpones cell injury by preserving ATP during ischemia. However, the only known inhibitors of F1F0-ATPase are large proteins or peptides which are not orally bioavailable.
The instant invention provides N-substituted-N′-(1-phenyl-2-heteraryl)ethyl-guanidine compounds including cyanoguanidine and benzoylguanidine compounds that are potent and selective inhibitors of F1F0-ATP hydrolase. The compounds of the present invention are useful in treating or preventing conditions associated with ischemia, particularly myocardial ischemia and associated conditions, such as muscle cell damage, necrosis, and cardiac arrhythmias. Also, in view of their inhibitory activity, the inventive compounds may be used to treat cancer and tumor growth. Cyano-guanidine based compounds for treating various other indications (e.g., diseases relating to the CNS-system, gastric secretion, inflammation, HIV, etc.) are disclosed in Shimada et al, “Synthesis and Gastric Antisecretory Activity of N-Cyano-N′(phenyl-pyridinylmethyl)guanidine Derivatives,” Chem. Pharm. Bull., Vol. 32(12), (1984), at pp. 4893-4906; WO 00/35449, “N-Ureidoalkyl-Piperidines as Modulators of Chemokine Receptor Activity,” to Du Pont Pharmaceuticals Co.; U.S. Pat. No. 5,478,845, “Piperidine Derivatives,” issued Dec. 26, 1995 and assigned to Novo Nordisk A/S; WO 93/05026, “Peptide Isoters Containing a Heterocycle as H.I.V. Inhibitors,” to Smith-Kline Beecham Corp.; and WO 00/43415, “Compounds which Inhibit Leukocyte Adhesion Mediated by VLA-4,” to Elan Pharmaceuticals, Inc. Cyano-guanidine compounds useful for lowering blood pressure or treating thrombotic or platelet aggregating conditions are disclosed in U.S. Pat. No. 5,521,177, U.S. Pat. No. 5,482,948, and WO 96/23771.
Each of the patents, patent applications and publications referred to in this application are incorporated herein by reference.